When do people believe that biological explanations, such as genes, brain damage, or abnormal hormones, mitigate punishment for crimes? We propose the way in which biology is viewed as impacting the true self of the actor—who the actor really is, deep down—is the key element for predicting biologically-based mitigation. Across four preregistered studies, 4,066 American adults learned of different biological explanations for crimes and judged punishment, fault, and blame. We show, while some biological explanations mitigate punishment and responsibility, general ascriptions to genes do not. Participants viewed external events like traumatic brain injury as a disconnect between the true self and the peripheral self, whereas they did not for genetic ascriptions. People interprete general genes-based explanations for crimes as indicating that the perpetrators true self was violent or dangerous, while other biological explanations did not impugn the actor’s true self. Only when genetic bases are described as mutations do genes become mitigating factors. In these latter cases, the actor is not judged as harshly because the violent crime could be attributed to aspects peripheral to the true self. Therefore, biological explanations differ in the extent to which they implicate the true self. These results help to clear up when biological explanations do and do not appear to mitigate responsibility for crimes: When the aspect of biology in question is viewed as part of the true self, it will not mitigate blame; but when the biological aspect is viewed as more peripheral, the blame seems to be mitigating.